To clarify the genetic components of human diabetes, a prospective study of the offspring of two diabetic parents and the apparently unaffected monozygotic twins with a diabetic twin mate will be continued and extended. Emphasis will be placed upon the determination of histocompatibility antigens and the relationships of these antigens to the presence or absence of overt diabetes and/or carbohydrate intolerance as evaluated by oral glucose tolerance test and other appropriate perturbations. Detailed evaluations of serum insulin, plasma glucagon and serum growth hormone responses will be made and related to histocompatibility antigens. Extensive evaluations of plasma cholesterol, HDL cholesterol and triglycerides will also be determined and related to the metabolic-hormonal aspects. In all of these prospective studies, glycosylated hemoglobin would be evaluated at least three times per year in all study groups and in appropriate normal controls. To determine the relationship between the degree of diabetes (from frank overt diabetes to mild chemical diabetes) on capillary morphology, muscle capillary basement membrane thickness will be evaluated by electron microscopy in study subjects. The mechanism of insulin secretion in these groups (generally characterized by a small but significant defect in insulin release) will be pursued by evaluating insulin secretion following the administration of not only glucose but also various hexoses other than glucose and evaluating the subsequent insulin responses, glucose utilization ad also by gastric inhibitory polypeptide determinations.